Development of novel molecular diagnostic and therapeutic tools based on genomic information of malignant mesothelioma
| Project/Area Number |
16H04706
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor diagnostics
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| Research Institution | Aichi Cancer Center Research Institute |
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Principal Investigator |
SEKIDO Yoshitaka 愛知県がんセンター(研究所), 分子腫瘍学分野, 副所長兼分野長 (00311712)
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| Co-Investigator(Kenkyū-buntansha) |
村上 優子 (渡並優子) 順天堂大学, 医学部, 准教授 (70405174)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2016: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
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| Keywords | 悪性中皮腫 / ゲノム異常 / シグナル伝達 / 新規治療戦略 / がん抑制遺伝子 / ゲノム解析 / 遺伝子 / トランスレーショナルリサーチ |
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| Outline of Final Research Achievements |
Malignant mesothelioma (MM) is a very aggressive tumor. The underlying key genetic mutations in MM cells mainly occur in several distinct tumor suppressor genes, which include the NF2 and BAP1 genes. In this project, we found that the inactivation of NF2 activates TAZ transcriptional coactivator, which results in expression of interleukin 1B. We also demonstrated that the suppression of IL1B inhibits MM cell proliferation. Meanwhile, we found that synthetic lethal phenotype is inducible in BAP1-mutated MM cells by targeting the other specific genes. These findings strongly suggested that different molecular approaches may be applied to develop new therapeutic modalities against MM.
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| Academic Significance and Societal Importance of the Research Achievements |
悪性中皮腫はがん遺伝子のドライバー変異が極めて稀であり、キナーゼ阻害剤などの分子標的剤はほとんど奏功しない。がん抑制遺伝子の変異が主体である悪性中皮腫に対しては、全く別の治療戦略の構築が必要と考えられる。今回、NF2-ヒッポシグナル伝達系が不活性化することにより活性化されるシグナル伝達系（インターロイキン1B）を標的とするアプローチ、さらにBAP1遺伝子変異に対して合成致死の表現型を誘導する遺伝子を標的するアプローチを見出すことができ、両者とも極めて有望な治療戦略であることが明らかとなった。
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Report
(4 results)
Research Products
(39 results)
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[Journal Article] Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model.2018
Author(s)
Ohara Y, Chew SH, Misawa N, Wang S, Somiya D, Nakamura K, Kajiyama H, Kikkawa F, Tsuyuki Y, Jiang L, Yamashita K, Sekido Y, Lipson KE, Toyokuni S.
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Journal Title
Oncotarget
Volume: 9
Issue: 26
Pages: 18494-18509
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Modeling mesothelioma utilizing human mesothelial cells reveals involvement of phospholipase-C beta 4 in YAP-active mesothelioma cell proliferation2016
Author(s)
T. Kakiuchi, T. Takahara, Y. Kasugai, K. Arita, N. Yoshida, K. Karube, M. Suguro, K. Matsuo, H. Nakanishi, T. Kiyono, S. Nakamura, H. Osada, Y. Sekido, M. Seto, S.Tsuzuki
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Journal Title
Carcinogenesis
Volume: -
Issue: 11
Pages: 1098-1109
DOI
Related Report
Peer Reviewed
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[Journal Article] Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma2016
Author(s)
S. Wang, L. Jiang, Y. Han, S.H. Chew, Y. Ohara, S. Akatsuka, L. Weng, K. Kawaguchi, T. Fukui, Y. Sekido, K. Yokoi, S. Toyokuni
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Journal Title
Oncotarget
Volume: 7
Issue: 43
Pages: 69565-69578
DOI
Related Report
Peer Reviewed / Open Access
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